2-(2-bromo-4-fluorophenyl)acetonitrile

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Add potassium hydroxide (8.39 g, 150 mmol) and tetrabutylamine bromide (0.3 g, catalytic) to a solution of 2-(2-bromo-4-fluorophenyl)acetonitrile (4 g, 18.69 mmol) and 1,3-dibromopropane (4.15 g, 20.5 mmol) in toluene (20 mL). Stir it at 100° C. temperature for 2 h. Dilute the mixture with water and extract with ethyl acetate. Wash the organic layer with 1 N HCl and aqueous saturated sodium chloride. Dry over magnesium sulfate. Remove the organic solvent to give the crude product. Distill to give 1-(2-bromo-4-fluorophenyl)cyclobutanecarbonitrile (boiling point 110-120° C./0.3 Torr.) (1.5 g, 31%). MS (GC) m/z 253 [M]+. extract with ethyl acetate Wash the organic layer with 1 N HCl and aqueous saturated sodium chloride Dry over magnesium sulfate Remove the organic solvent to give the crude product Distill

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Add sodium hydride (1 g, 42.1 mmol) to a stirred solution of (2-bromo-4-fluoro-phenyl)-acetonitrile (3 g, 14 mmol) in 10 mL of dimethyl formamide (DMF) at 0° C. Stir the mixture at 0° C. to RT for half an hour. Add methyl iodide (6 g, 42 mmol). Stir for another 30 min. Quench the reaction with water. Extract the product into DCM. Dry the organic phase over sodium sulfate and concentrate to give an oily residue. Purify the residue by flash column chromatography (FCC) (hexane to 20% ethyl acetate in hexane as gradient elute) to give the title compound as a white solid (2.2 g, 65%). 1H NMR (400 MHz, CDCl3) δ 7.41-7.47 (m, 2H), 7.03-7.08 (m, 1H), 1.88 (s, 6H). Stir for another 30 min Quench the reaction with water Extract the product into DCM Dry the organic phase over sodium sulfate concentrate to give an oily residue Purify the residue by flash column chromatography (FCC) (hexane to 20% ethyl acetate in hexane as gradient elute)

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of sodium methoxide in methanol (25%, 34 mL, 157 mmol) was combined with toluene (200 mL). The methanol was then distilled off at 90° C. using a Dean-Stark trap. After the solution was cooled to 70° C., 2-bromo-4-fluorobenzeneacetonitrile (21.4 g, 100 mmol) dissolved in ethyl acetate (40 mL) was added from a dropping funnel over 20 min with mechanical stirring. At this point additional toluene (150 mL) was added to facilitate stirring of a voluminous light pink precipitate. The reaction mixture was poured into water, and the organic phase was separated. The aqueous phase was acidified and extracted with ethyl acetate. The ethyl acetate phase was dried and concentrated under reduced pressure to provide the intermediate compound α-acetyl-2-bromo-4-fluorobenzeneacetonitrile as a crude oil. The methanol was then distilled off at 90° C. was added from a dropping funnel over 20 min with mechanical stirring the organic phase was separated extracted with ethyl acetate The ethyl acetate phase was dried concentrated under reduced pressure

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of sodium methoxide in methanol (25%, 34 mL, 157 mmol) was combined with toluene (200 mL). The methanol was then distilled off at 90° C. using a Dean-Stark trap. After the solution was cooled to 70° C., 2-bromo-4-fluorobenzeneacetonitrile (21.4 g, 100 mmol) dissolved in ethyl acetate (40 mL) was added from a dropping funnel over 20 min with mechanical stirring. At this point additional toluene (150 mL) was added to facilitate stirring of a voluminous light pink precipitate. The reaction mixture was poured into water, and the organic phase was separated. The aqueous phase was acidified and extracted with ethyl acetate. The ethyl acetate phase was dried and concentrated under reduced pressure to provide the intermediate compound α-acetyl-2-bromo-4-fluorobenzeneacetonitrile as a crude oil. The methanol was then distilled off at 90° C. was added from a dropping funnel over 20 min with mechanical stirring the organic phase was separated extracted with ethyl acetate The ethyl acetate phase was dried concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of potassium hydroxide (18.7 ml, 18.7 mmol) in methanol and hydroxylamine hydrochloride (18.7 ml, 18.7 mmol) in methanol were mixed, filtered and added to 2-(2-bromo-4-fluorophenyl)acetonitrile (1 g, 4.67 mmol) in MeOH and stirred at 60° C. for 24 h, evaporated to dryness. The residue was dissolved in chloroform (30.0 ml) and to this was added dimethyl but-2-ynedioate (730 mg, 5.14 mmol). The mixture was stirred at 60° C. for 24 h, cooled and evaporated to dryness. The residue was dissolved in xylene (10 ml) and heated at 120° C. for 2 h in microwave oven. The cooled residue was evaporated to dryness and then triturated with EtOAc, filtered and washed with Et2O to give the title compound as a brown solid (0.21 g; 12%). LCMS: m/z=358 (MH+). filtered evaporated to dryness The residue was dissolved in chloroform (30.0 ml) The mixture was stirred at 60° C. for 24 h cooled evaporated to dryness The residue was dissolved in xylene (10 ml) heated at 120° C. for 2 h in microwave oven The cooled residue was evaporated to dryness triturated with EtOAc filtered washed with Et2O

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Add potassium hydroxide (8.39 g, 150 mmol) and tetrabutylamine bromide (0.3 g, catalytic) to a solution of 2-(2-bromo-4-fluorophenyl)acetonitrile (4 g, 18.69 mmol) and 1,3-dibromopropane (4.15 g, 20.5 mmol) in toluene (20 mL). Stir it at 100° C. temperature for 2 h. Dilute the mixture with water and extract with ethyl acetate. Wash the organic layer with 1 N HCl and aqueous saturated sodium chloride. Dry over magnesium sulfate. Remove the organic solvent to give the crude product. Distill to give 1-(2-bromo-4-fluorophenyl)cyclobutanecarbonitrile (boiling point 110-120° C./0.3 Torr.) (1.5 g, 31%). MS (GC) m/z 253 [M]+. extract with ethyl acetate Wash the organic layer with 1 N HCl and aqueous saturated sodium chloride Dry over magnesium sulfate Remove the organic solvent to give the crude product Distill

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Add sodium hydride (1 g, 42.1 mmol) to a stirred solution of (2-bromo-4-fluoro-phenyl)-acetonitrile (3 g, 14 mmol) in 10 mL of dimethyl formamide (DMF) at 0° C. Stir the mixture at 0° C. to RT for half an hour. Add methyl iodide (6 g, 42 mmol). Stir for another 30 min. Quench the reaction with water. Extract the product into DCM. Dry the organic phase over sodium sulfate and concentrate to give an oily residue. Purify the residue by flash column chromatography (FCC) (hexane to 20% ethyl acetate in hexane as gradient elute) to give the title compound as a white solid (2.2 g, 65%). 1H NMR (400 MHz, CDCl3) δ 7.41-7.47 (m, 2H), 7.03-7.08 (m, 1H), 1.88 (s, 6H). Stir for another 30 min Quench the reaction with water Extract the product into DCM Dry the organic phase over sodium sulfate concentrate to give an oily residue Purify the residue by flash column chromatography (FCC) (hexane to 20% ethyl acetate in hexane as gradient elute)

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of sodium methoxide in methanol (25%, 34 mL, 157 mmol) was combined with toluene (200 mL). The methanol was then distilled off at 90° C. using a Dean-Stark trap. After the solution was cooled to 70° C., 2-bromo-4-fluorobenzeneacetonitrile (21.4 g, 100 mmol) dissolved in ethyl acetate (40 mL) was added from a dropping funnel over 20 min with mechanical stirring. At this point additional toluene (150 mL) was added to facilitate stirring of a voluminous light pink precipitate. The reaction mixture was poured into water, and the organic phase was separated. The aqueous phase was acidified and extracted with ethyl acetate. The ethyl acetate phase was dried and concentrated under reduced pressure to provide the intermediate compound α-acetyl-2-bromo-4-fluorobenzeneacetonitrile as a crude oil. The methanol was then distilled off at 90° C. was added from a dropping funnel over 20 min with mechanical stirring the organic phase was separated extracted with ethyl acetate The ethyl acetate phase was dried concentrated under reduced pressure